Gene expression profiles have identified five major molecular subtypes of breast cancer (Luminal A, Luminal B, Basal-like, HER2+/ER-, Normal Breast-like) that show significant differences in survival. Mounting evidence also suggests that these subtypes vary in their responsiveness to chemotherapeutics and biologic agents. In fact, specific drug targets, like HER1 and HER2, within different subtypes suggests that logical combinations of chemotherapeutics and biologic agents may be subtype-specific, which must be empirically evaluated. Nonetheless, picking the right chemotherapeutic(s) and biologic agent combination for each subtype has yet to be experimentally or clinically determined. Therefore, we propose here to identify efficacious combination therapies for the tumor subtypes by testing at least 8 different regimens on a preclinical animal models system composed of primary human tumor xenografts, breast tumor-derived cell lines grown as xenografts, and transgenic mice that develop mammary carcinomas with known molecular subtypes. These experimental results will be augmented with human clinical trial data from several different trials that test a variety of chemotherapy and biologic therapy combinations, which should ultimately allow us to develop genomic assays that could be used to select patients for specific chemotherapy regimens, and to identify tumor subtype sensitivities that will be prospectively tested in the next generation of clinical trials.